Controlled release pharmaceutical compositions for acid-labile drugs

ABSTRACT

An enteric-coated oral dosage form comprising an acid labile active pharmaceutical ingredient where the composition is substantially free of monomeric phthalic acid esters and synthetic oils is described herein. Also provided are methods for making and using the enteric-coated oral dosage form. The disclosed pharmaceutical compositions comprise an enteric coating which includes at least one plasticizer, at least one film-forming agent and optionally at least one anti-sticking agent.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Nos.60/708,526 and 60/708,692 which were both filed Aug. 15, 2005 and areboth hereby incorporated by reference.

FIELD OF THE INVENTION

Described herein is a pharmaceutical composition in an oral dosage formand methods for making and using the same. More specifically, describedherein are pharmaceutical compositions for acid-labile activepharmaceutical ingredients in an enteric-coated oral dosage form wherethe dosage form is substantially free of both monomeric phthalic acidester plasticizers and synthetic oils.

BACKGROUND

Numerous active pharmaceutical ingredients (API) are know to beincompatible with the acidic environment present in mammalian, such ashuman, stomachs. Due to this incompatibility, it can be advantageous toprotect these acid-labile compounds until such time as they reach apoint in the GI tract having a pH which is more compatible with theparticular API. Controlled or delayed release pharmaceuticalcompositions for acid-labile drugs, in particular for acid-labile drugsthat need to be delivered to the upper intestine of a mammal and whereexposure of the acid-labile API to the acidic gastric environment is tobe avoided, is often desirable.

One such acid-labile API which is advantageously delivered to the humanduodenum is pancreatin. Pancreatin is a substance which is derived frommammalian pancreas glands and comprises different digestive enzymes suchas lipases, amylases and proteases. Pancreatin has been used to treatpancreatic exocrine insufficiency (PEI) which is often associated withcystic fibrosis, chronic pancreatitis, post-pancreatectomy,postgastrointestinal bypass surgery (e.g. Billroth II gastroenterostomy)and ductal obstruction from neoplasm (e.g. of the pancreas or commonbile duct). Pancreatin microspheres are the treatment of choice fordiseases or disorders caused by digestive enzyme deficiency in mammalssuch as humans. This is due to the fact that high-performance pancreatinmicrosphere products like Creon™ provide a therapeutically effectiveload of active enzymes while at the same time providing properly sizedmicrospheres capable of targeting the optimal location in the digestivetract where digestive enzyme activity will be needed, in particular theupper intestine such as the duodenum.

Recently, governmental health authorities have initiated a reassessmentof the compatibility of certain pharmaceutical excipients which hadpreviously been used in the formulation of pancreatin-containingproducts and have provided advice concerning the use of specificpharmaceutical excipients such as mineral oil (see e.g. US Code ofFederal Regulations, 21 CFR §201.302) and dibutyl phthalate (see e.g.directive 2003/36/EC of the European Parliament and the Council of 26May 2003 amending for the 25^(th) time Council Directive 76/769/EEC). Asa result, it is now recommended that mineral oil not be providedindiscriminately to either pregnant women or infants. Similarly, healthauthorities today recommend restricting the use of dibutyl phthalate.Therefore, a need exists to provide patients with formulations ofpharmaceutical products which would be responsive to the current adviceof health authorities.

Some controlled release pharmaceutical preparations and/or methods forpreparing them are disclosed in EP 0063014 or U.S. Pat. No. 5,725,880.

Pharmaceutical preparations which may comprise pancreatin and an entericcoating are disclosed in DE 19907764; EP 0021129 (U.S. Pat. No.4,280,971); EP 0035780; EP 0583726 (U.S. Pat. No. 5,378,462); U.S. Pat.No. 5,225,202; U.S. Pat. No. 5,750,148; U.S. Pat. No. 6,224,910; US2002/0146451 and WO 02/40045.

U.S. Pat. No. 4,786,505 discloses pharmaceutical preparations for oraluse.

Published patent application US 2004/0213847 discloses delayed releasepharmaceutical compositions containing proton pump inhibitors.

Published patent application US 2002/061302 discloses the use ofphysiologically acceptable enzyme mixtures for the treatment ofdiabetes.

SUMMARY

Accordingly, one embodiment disclosed herein is an enteric-coated oraldosage form containing an acid-labile API where the dosage form issubstantially free of monomeric phthalic acid ester plasticizers andsynthetic oils.

Other objects, features and advantages will be set forth in the DetailedDescription that follows, and in part will be apparent from thedescription or may be learned by practice of the claimed invention.These objects and advantages will be realized and attained by theprocesses and compositions particularly pointed out in the writtendescription and claims hereof.

DETAILED DESCRIPTION

While the present invention is capable of being embodied in variousforms, the description below of several embodiments is made with theunderstanding that the present disclosure is to be considered as anexemplification of the invention, and is not intended to limit thedisclosure to the specific embodiments and examples illustrated. Theheadings used throughout this disclosure are provided for convenienceonly and are not to be construed to limit the disclosure in any way.Embodiments illustrated under any heading may be combined withembodiments illustrated under the same or any other heading.

It has now been surprisingly discovered that a controlled releasepharmaceutical composition comprising acid-labile drugs, such aspancreatin, in the upper intestine can be achieved by providing anenteric-coated oral dosage form wherein the enteric-coating comprises atleast one plasticizer and at least one film-forming agent as describedin more detail below. The new enteric coating as disclosed herein issubstantially free of both, monomeric phthalic acid ester plasticizers,such as dibutyl phthalate, and synthetic oils, such as paraffins ormineral oils, while at the same time providing the desired targetedrelease and storage stability. The enteric coating as disclosed hereinfurther provides beneficial properties which are comparable to therespective properties of pharmaceutical compositions which containsdibutyl phthalate and synthetic oil in the formulation.

It is therefore provided herein an enteric coating comprising

-   -   a) one or more film-forming agents;

b) at least one plasticizer in an amount of greater than about 1.5% byweight relative to the one or more film-forming agents wherein theplasticizer is substantially free of monomeric phthalic acid esters; and

-   -   c) optionally at least one anti-sticking agent.

The enteric coating can be applied to oral dosage forms of acid-labiledrugs, such as pancreatin, which need to be delivered to the GI tract ata location having a pH higher than the stomach. By applying the entericcoating as disclosed herein to oral dosage forms of acid-labile drugs,controlled release pharmaceutical compositions (CRPC) of the acid-labiledrugs can be achieved.

Film-forming agent(s), plasticizer(s) and anti-sticking agent(s) (whenpresent) as used for preparing the enteric coating are hereinaftercommonly referred to as “non-solvent coating constituents”.

Suitable film-forming agents include agar, Carbopol™ (carbomer) polymers(i.e. high molecular weight, crosslinked, acrylic acid-based polymers),carboxymethyl cellulose, carboxymethylethyl cellulose, carrageen,cellulose acetate phthalate, cellulose acetate succinate, celluloseacetate trimelliate, chitin, corn protein extract, ethyl cellulose, gumarabic, hydroxypropyl cellulose, hydroxypropylmethyl acetate succinate,hydroxypropyl methylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, methacrylic acid-ethylmethacrylate-copolymer, methyl cellulose, pectin, polyvinyl acetatephthalate, polivinyl alcohol, shellac, sodium alginate, starch acetatephthalate and/or styrene/maleic acid copolymer or mixtures of saidfilm-forming polymers. Cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate and/or methacrylic acid-ethylmethacrylate-copolymer are the preferred film-forming agents. Mostpreferred is hydroxypropyl methylcellulose phthalate, e.g. HP 55 orHPMCP HP-50. Synthetic oils are not to be regarded as preferredfilm-forming agents. The foregoing list of film-forming agents is notmeant to be exhaustive but merely illustrative, as a person or ordinaryskill in the art would understand that many other film-forming agents orcombination of film-forming agents could also be used.

The plasticizer(s) may generally be present in an amount greater thanabout 1.5%, and typically in an amount between about 2% and about 20% byweight, relative to the film-forming agent. The plasticizer may containsaturated linear monohydric alcohols having 12 to 30 carbon atoms. Morespecifically, acceptable plasticizers include lauryl alcohol, tridecylalcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, heptadecylalcohol, stearyl alcohol, nonadecyl alcohol, arachic alcohol, behenylalcohol, carnaubyl alcohol, ceryl alcohol, corianyl alcohol, melissylalcohol, acetyl tributyl citrate, dibutyl sebacate, fatty acid esters ofglycerol, glycerol, polyethylene glycol, propyleneglycol, sorbitan fattyacids, triacetin, triethyl citrate and mixtures of said plasticizers.Preferred plasticizers are cetyl alcohol, stearyl alcohol, triethylcitrate and mixtures thereof. When cetyl alcohol is used as a singleplasticizer, it may be present in an amount of greater than about 1.5%,typically in an amount of about 2% to about 15%, preferably about 2% toabout 10%, by weight relative to the film-forming agent. When triethylcitrate is used as a single plasticizer, it may be present in an amountbetween about 5% and about 20%, preferably between about 12% and about15%, by weight relative to the film-forming agent. Synthetic oils andmonomeric phthalic acid esters are not to be regarded as suitableplasticizers. The foregoing list of plasticizers is not meant to beexhaustive but merely illustrative, as a person or ordinary skill in theart would understand that many other plasticizers or combination ofplasticizers could also be used so long as they are substantially freeof both synthetic oils and monomeric phthalic acid esters.

In one embodiment the plasticizer is comprised of cetyl alcohol andtriethyl citrate which are collectively present in an amount of greaterthan about 3%, typically in an amount of about 4% to about 20%, inparticular between about 6% and about 15%, more particularly betweenabout 7% and about 10%, by weight in relation to the film-forming agent.The weight to weight ratio of cetyl alcohol to triethyl citrate whenboth are present may be from about 0.05:1 to about 1:1, for example0.1:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1 or 0.9:1. Inparticular, the ratio of cetyl alcohol to triethyl citrate may be fromabout 0.25:1 to about 0.5:1, preferably from about 0.3:1 to about0.45:1, more preferably from about 0.35:1 to about 0.4:1, and even morepreferably from about 0.38:1 to about 0.4:1 (w/w).

The enteric coating optionally comprises an anti-sticking agent.Suitable anti-sticking agents include dimethicone and castor oil.Dimethicone, in particular dimethicone 1000, is the preferredanti-sticking agent. The amount of anti-sticking agent (if present) inthe enteric coating is between about 1.5% and about 3% by weightrelative to the film-forming agent. Synthetic oils are not to beregarded as preferred anti-sticking agents. The foregoing list ofanti-sticking agents is not meant to be exhaustive but merelyillustrative, as a person or ordinary skill in the art would understandthat many other anti-sticking agents or combination of anti-stickingagents could also be used.

Additional embodiments are also located in U.S. Pat. No. ______ filed onAug. 15, 2006 and claiming the benefit of U.S. Provisional ApplicationNos. 60/708,526 and 60/708,692 which were both filed on Aug. 15, 2005.U.S. Pat. No. ______ is hereby incorporated by reference.

The term “synthetic oils” means unsaponifiable hydrocarbons or mixturesof hydrocarbons and comprises e.g. liquid and solid paraffins, inparticular liquid paraffins (mineral oils), more particularly highlyliquid paraffin (light mineral oil).

The phrase “substantially free of synthetic oils” means that themanufacturing processes described herein and used to make the entericcoating or the enteric coated oral dosage forms of acid-labile drugswhere applicable do not utilize one or more synthetic oils as anexcipient although synthetic oils may be present as pharmaceuticallyacceptable trace contaminants in the API, binding agent(s), entericcoating constituents, organic solvents and/or excipients which are usedto manufacture the enteric coating and/or the enteric coated oral dosageforms of acid-labile drugs described herein.

The phrase “substantially free of monomeric phthalic acid esters” meansthat the manufacturing processes described herein and used to make theenteric coating or the enteric coated oral dosage forms of acid-labiledrugs where applicable do not utilize one or more monomeric phthalicacid esters (e.g. dibutyl phthalate) as an excipient although monomericphthalic acid esters may be present as pharmaceutically acceptable tracecontaminants in the API, binding agent(s), enteric coating constituents,organic solvents and/or excipients which are used to manufacture theenteric coating and/or the enteric coated oral dosage forms ofacid-labile drugs described herein.

Examples of acid-labile drugs which may be coated with the enericcoating as disclosed herein are e.g.(+)-N-{3-[3-(4-fluorophenoxy)phenyl]-2-cyclopenten-1-yl}-N-hydroxyurea,amylase, aureomycin, bacitracin, beta carotene, cephalosporins,chloromycetin, cimetidine, cisapride, cladribine, clorazepate,deramciclane, didanosine, digitalis glycosides, dihydrostreptomycin,erythromycin, etoposide, famotidine, hormones (in particular estrogens,insulin, adrenalin and heparin), lipase, milameline, novobiocin,pancreatin, penicillin salts, polymyxin, pravastatin, progabide,protease, quinapril, quinoxaline-2-carboxylic acid,[4-(R)-carbamoyl-1-(S-3-fluorobenzyl-2-(S),7-dihydroxy-7-methyloctyl]amide,quinoxaline-2-carboxylicacid[1-benzyl-4-(4,4-difluoro-1-hydroxy-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide,ranitidine, streptomycin, subtilin, sulphanilamide and acid-labileproton pump inhibitors like esomeprazole, lansoprazole, minoprazole,omeprazole, pantoprazole or rabeprazole. Amylase, lipase and proteasemay be coated together or separately. Amylases, lipases and proteaseswhich are suitable as digestive enzyme supplement or digestive enzymesubstitute in mammals, particularly humans, are preferred. Amylase,lipase and/or protease may be derived from microbial or animal, inparticular mammalian, sources. Pancreatin is the preferred acid-labiledrug. The foregoing list of acid-labile drugs is not meant to beexhaustive, but merely illustrative as a person of ordinary skill in theart would understand that many other acid-labile drugs or combination ofacid-labile drugs could also be used.

Pancreatin is a mixture of different physiologically active endogenousingredients which is derived from mammalian pancreas glands andcomprises as its main constituents different digestive enzymes likelipases, amylases and proteases. Mammalian pancreatic lipase istypically used as a digestive enzyme supplement or substitute for thetreatment of PEI but pancreatic proteases and amylases also contributeto the therapeutic value of pancreatin. Pancreatin for pharmaceuticaluse is typically of bovine or porcine origin. Porcine pancreatin ispreferred.

The oral dosage form containing the acid-labile drugs may be in the formof, for example, capsules, granules, granulates, micropellets,microspheres, microtablets, pellets, pills, powders and/or tablets. Forthe purposes of this invention, the prefix “micro” is used to describean oral dosage form if the diameter of the oral dosage form or all ofits dimensions (length, height, width) is equal to or below about 5 mm.

In one embodiment the enteric coating comprises between about 20% andabout 30% by weight, more preferably between about 22% and about 26% byweight, yet more preferably between about 22.5% and about 25% by weightof the total composition of the enteric coated oral dosage form or CRPC.

In one embodiment, the oral dosage form is a pancreatin micropellet orpancreatin microsphere which comprise between about 10% and about 95% byweight of pancreatin, between about 5% and about 90% by weight of atleast one pharmaceutically acceptable binding agent and between 0% andabout 10% by weight of at least one pharmaceutically acceptableexcipient. More specifically, pancreatin micropellet cores can beproduced by the process described herein which comprise between about70% and about 90% by weight of pancreatin, between about 10% and about30% by weight of at least one pharmaceutically acceptable binding agentand between 0% and about 5% by weight of at least one pharmaceuticallyacceptable excipient. In one embodiment, pancreatin micropellet corescan be produced which comprise between about 70% and about 90% by weightpancreatin, and between about 10% and about 30% by weight of at leastone pharmaceutically acceptable binding agent. In one embodiment thepancreatin micropellet or pancreatin microsphere is approximatelyspherical and has a diameter between about 0.5 mm and about 2.0 mm.

Examples of pharmaceutically acceptable binding agents includepolyethylene glycol 1500, polyethylene glycol 2000, polyethylene glycol3000, polyethylene glycol 4000, polyethylene glycol 6000, polyethyleneglycol 8000, polyethylene glycol 10000, hydroxypropyl methylcellulose,polyoxyethylen, copolymers of polyoxyethylen-polyoxypropylen andmixtures of said organic polymers. The foregoing list ofpharmaceutically acceptable binding agents is not meant to beexhaustive, but merely illustrative as a person of ordinary skill in theart would understand that many other pharmaceutically acceptable bindingagents or combination of binding agents could also be used. Polyethyleneglycol 4000 is the preferred pharmaceutically acceptable binding agent.

Examples of suitable pharmaceutically acceptable excipients includegliding agents like magnesium stearate or calcium stearate, stearicacid, talcum and/or starch; fillers like calcium phosphate, corn starch,dextrans, dextrin, hydrated silicon dioxide, microcrystalline cellulose,kaolin, lactose, mannitol, polyvinyl pyrrolidone, precipitated calciumcarbonate, sorbitol and/or talcum; disintegrating agents like Aerosil™(silicic acid), alginic acid, amylose, calcium alginate, calciumcarbonate, formaldehyde gelatin, pectic carbonate, sago starch, sodiumbicarbonate and/or starch; and/or moisturizers like glycerol and/orstarch. The foregoing list of pharmaceutically acceptable excipients isnot meant to be exhaustive, but merely illustrative as a person orordinary skill in the art would understand that many otherpharmaceutically acceptable excipients or combination of excipientscould also be used. For the purposes of the present disclosure,synthetic oils and monomeric phthalic acid esters are not to be regardedas suitable pharmaceutically acceptable excipients. In one embodiment,the pancreatin micropellets or pancreatrin microspheres contain nopharmaceutically acceptable excipients, but can optionally contain agreater amount of pancreatin.

In one embodiment, pancreatin micropellets can be prepared by amanufacturing process comprising the steps of:

-   -   a) preparing an extrudable mixture comprising:        -   i. about 10% to about 95% pancreatin;        -   ii. about 5% to about 90% of at least one pharmaceutically            acceptable binding agent;        -   iii. 0% to about 10% of at least one pharmaceutically            acceptable excipient; and        -   iv. one or more enzyme-friendly organic solvents in an            amount sufficient to form an extrudable mixture; wherein the            percentages of components are weight to weight of the            pancreatin micropellets;    -   b) creating pancreatin micropellets from the extrudable mixture;    -   c) forming the pancreatin micropellets into approximately        spherical or approximately ellipsoidal shape in the presence of        additional enzyme-friendly organic solvent; and    -   d) removing the one or more enzyme-friendly organic solvents        from the pancreatin micropellets such that the pancreatin        micropellets are substantially free of the one or more        enzyme-friendly organic solvents.

Process variations wherein the pancreatin micropellets are substantiallyfree of synthetic oils are preferred.

Further, process variations wherein the pharmaceutically acceptableexcipients are present in an amount of 0% are preferred.

The amounts of pancreatin, pharmaceutically acceptable binding agent(s),pharmaceutically acceptable excipient(s) and/or enzyme-friendly organicsolvent may be varied by those skilled in the art to arrive at thepancreatin micropellets having the preferred composition andcharacteristics as indicated herein.

Enzyme-friendly organic solvents facilitate mixing and other processingprocedures and may afterwards be removed, for example, by drying.Typically, after removal of the enzyme-friendly organic solvents, acertain amount of solvent remains in the pancreatin micropellet cores.The remaining solvent in the micropellet cores can compriseenzyme-friendly organic solvents, water, or a mixture of enzyme-friendlyorganic solvents with water. If water is present as a solvent, this willtypically have been present in the pancreatin which was used as thestarting material. The amount of solvent present in the pancreatinmicropellet cores after removal of the enzyme-friendly organic solventsis typically less than about 5% and normally less than about 3% byweight of the pancreatin micropellet core.

Examples of suitable enzyme-friendly organic solvents are acetone,chloroform, dichloromethane or straight-chained or branchedC₁₋₄-alcohols, particularly methanol, ethanol, 1-propanol, 2-propanol,2-butanol, tert-butanol or mixtures of said solvents. 2-propanol is thepreferred enzyme-friendly organic solvent. For the purposes of thepresent disclosure, synthetic oils are not to be regarded as suitableenzyme-friendly organic solvents. The enzyme-friendly organic solvent istypically used in an amount of about 15% to about 35% by weight,preferably of about 20% to about 30% by weight, relative to the amountof pancreatin used. The foregoing list of suitable enzyme-friendlyorganic solvents is not meant to be exhaustive, but merely illustrativeas a person or ordinary skill in the art would understand that manyother enzyme-friendly organic solvents or combination of solvents couldalso be used. The amounts of pancreatin, pharmaceutically acceptablebinding agent(s), pharmaceutically acceptable excipient(s) and/orenzyme-friendly organic solvent may be varied by those skilled in theart to arrive at the pancreatin micropellets having the preferredcomposition as indicated herein.

The term “substantially free of enzyme-friendly organic solvents” meansthat the quantity of enzyme-friendly organic solvents present in theoral dosage form would be less than about 5% by weight.

Removal of the one or more enzyme-friendly organic solvents from theoral dosage form means that the oral dosage form is subject toconditions whereby it becomes substantially free from enzyme-friendlyorganic solvents. Removal of the enzyme-friendly organic solvents can beby methods known to those of ordinary skill in the art. The preferredmethod is by drying. Additionally, removal of the one or moreenzyme-friendly organic solvents would also typically result in the oraldosage form containing an amount of water which is less than about 5%and typically less than about 3% by weight.

In one embodiment the pancreatin micropellets are created in processstep b) by extrusion. Remarkably, an extrudable mixture is obtained evenwhen the mixture is substantially free of synthetic oils. In processstep b), if the creating of the micropellets from the extrudable mixtureis accomplished by means of extrusion, then the temperature preferablydoes not exceed about 70° C. during extrusion, more preferably thetemperature does not exceed about 50° C. Also, in the event ofextrusion, piercing dies are preferably used which have a hole diameterof about 0.5 to about 2.0 mm, preferably of about 0.7 to about 1.5 mm,and more preferably about 0.8 mm. Preferably, the pancreatin micropelletor pancreatin microsphere has a diameter of about 0.5 to about 2.0 mm,in particular of about 0.7 to about 1.5 mm, 0.8 mm. If the extrudablemixture is extruded, then the extrudate fragments are brought to asuitable length for the forming step. This can be done e.g. by means ofa cutting device arranged downstream to the extruding press in a mannerknown to the a person of ordinary skill in the art. The forming inprocess step c) can be carried out e.g. in a customary roundingapparatus. In the rounding apparatus, the extrudate fragments are thenformed into an approximately spherical or approximately ellipsoidalshape in the presence of additional enzyme-friendly organic solventwhich may be the same or different than the enzyme-friendly organicsolvent used in process step a).

When prepared substantially free of synthetic oils, processing of theextrudate fragments in the rounding apparatus is improved relative toother known processes which use synthetic oils. For example, a loweramount of enzyme-friendly organic solvent needs to be added when formingthe pancreatin micropellets into an approximately spherical orapproximately ellipsoidal shape and fewer of the extrudate fragmentsstick to parts of the rounding apparatus when the process is practicedwith an extruder and rounding apparatus.

The invention further provides a process for producing a CRPC which isan enteric coated oral dosage form of an acid-labile drug comprising thesteps of:

-   -   a. providing an oral dosage form of an acid-labile drug;    -   b. providing an enteric-coating solution comprising        -   i. one or more film-forming agents;        -   ii. at least one plasticizer in an amount of greater than            about 1.5% by weight relative to the one or more            film-forming agents wherein the plasticizer is substantially            free of monomeric phthalic acid esters;        -   iii. optionally, at least one anti-sticking agent; and        -   iv. one or more volatile organic solvents;    -   c. coating the oral dosage form with the enteric-coating        solution wherein the product temperature of the pancreatin        micropellet cores during coating is kept at a temperature        suitable to apply the enteric-coating solution;    -   d. drying the coated oral dosage form.

In the foregoing process for producing an enteric-coated oral dosageform of an acid-labile drug, the oral dosage form(s), the film-formingagent(s), the plasticizer(s), the anti-sticking agent(s) and theenzyme-friendly organic solvents generally have the meanings as setforth above.

Process step b) may be performed at a temperature between about 15° C.and about 60° C. Performing process step b) at ambient temperature (i.e.room temperature, approximately between about 20° C. and about 30° C.),is preferred. Examples of suitable enzyme-friendly organic solventsinclude acetone, 2-butanol, tert.-butanol, chloroform, dichloromethane,ethanol, methanol, 1-propanol, 2-propanol and mixtures of said solvents.Acetone, ethanol and 2-propanol or their mixtures are preferred asenzyme-friendly organic solvents. Acetone is most preferred. Theforegoing list of enzyme-friendly organic solvents in process step b) isnot meant to be exhaustive but merely illustrative, as a person orordinary skill in the art would understand that many otherenzyme-friendly organic solvents or combination of solvents could alsobe used.

The enzyme-friendly organic solvent is typically used in an amountbetween about 6 and about 10 times, preferably between about 7 and about8 times, the weight of the non-solvent coating constituents used toprepare the pancreatin micropellets. For example, if the non-solventcoating constituents make up to a total weight of about 1.5 g, thenabout 9 g to about 15 g of enzyme-friendly organic solvent may be usedin process step a).

The enteric coating optionally comprises an anti-sticking agent.Suitable anti-sticking agents include dimethicone and castor oil.Dimethicone, in particular dimethicone 1000, is the preferredanti-sticking agent. The anti-sticking agent is usually present in theenteric coating in an amount of between about 1.5% and about 3% byweight relative to the film-forming agent. Synthetic oils are not to beregarded as preferred anti-sticking agents. The foregoing list ofanti-sticking agents is not meant to be exhaustive but merelyillustrative, as a person or ordinary skill in the art would understandthat many other anti-sticking agents or combination of anti-stickingagents could also be used.

Due to the process for producing CRPCs, viz the coating process asdescribed herein, pharmaceutically acceptable residual amounts of theenzyme-friendly organic solvent(s) present in the enteric-coatingsolution may still be present in the final enteric coated oral dosageform. It is understood that CRPCs comprising pharmaceutically acceptableresidual amounts of enzyme-friendly organic solvent(s) are within thescope of the present invention.

In process step c) the product temperature of the oral dosage form, inone embodiment, is usually maintained between about 30° C. and about 60°C. while coating, preferably between about 32° C. and about 55° C., morepreferred between about 35° C. and about 50° C., most preferably betweenabout 37° C. and about 49° C. In process step c), when cetyl alcohol orboth cetyl alcohol and triethyl citrate are used the product temperatureof the oral dosage form is maintained between about 40° C. and about 46°C. Maintaining the product temperature of the oral dosage form withinthe preferred temperature ranges while coating results in improvedgastric-acid resistant properties of the CPRC, in particular when theenteric coating comprise cetyl alcohol and triethyl citrate asplasticizers. The coating in process step c) can be accomplished by anyprocess or method known to a person of ordinary skill in the art. Spraycoating is preferred. If the coating in process step c) is performed byspray coating, the spray rate can be between about 97 kg/h and about 115kg/h. Usually, process step c) is performed in a way that the entericcoating comprises between about 20% and about 30% by weight, preferablybetween about 22% and about 26% by weight and more preferably betweenabout 22.5% and about 25% by weight of the total composition of theenteric coated oral dosage form or CRPC. The exact parameters to beapplied in process step c) to achieve the desired enteric coating willdepend on the coating technique used. The person skilled in the artunderstands how to achieve coating films of a desired thickness whenusing different coating techniques.

Drying of the enteric-coated oral dosage form of the acid-labile drug inprocess step dd.) is preferably performed between about 30° C. and about90° C., preferably between about 30° C. and about 55° C., and preferablybetween about 35° C. and about 50° C. for a period of between about 1hour and about 60 hours, between about 6 hours and about 60 hours,preferably for a period of between about 6 hours and about 36 hours.

In one embodiment of the process for producing an enteric coated oraldosage form of an acid-labile drug, the acid-labile drug is pancreatin.Disclosed herein is a process for the manufacture of pancreatinmicropellets, comprising the steps of:

-   -   aa. providing pancreatin micropellet cores wherein the        pancreatin micropellet cores are substantially free of synthetic        oils;    -   bb. providing an enteric-coating solution comprising        -   i. one or more film-forming agents;        -   ii. a plasticizer in an amount greater than about 1.5% by            weight relative to the one or more film-forming agents            film-forming agents wherein the plasticizer is substantially            free of monomeric phthalic acid esters; and        -   iii. optionally, at least one anti-sticking agent, and        -   iv. one or more enzyme-friendly organic solvent(s);    -   cc. coating the pancreatin micropellet cores with the        enteric-coating solution wherein the temperature of the        pancreatin micropellet cores during coating is kept at a        temperature suitable for applying the enteric-coating solution;        and    -   dd. drying the coated pancreatin micropellet cores.

In the foregoing process for producing pancreatin micropellets, thefilm-forming agent(s), the plasticizer(s), the anti-sticking agent(s)and the enzyme-friendly organic solvents generally have the meanings aspreviously set forth.

Due to the process for producing pancreatin micropellets, viz. thecoating process as described herein, pharmaceutically acceptableresidual amounts of the enzyme-friendly organic solvent(s) present inthe enteric-coating solution may still be present in the pancreatinmicropellet after drying. It is understood that pancreatin micropelletscomprising pharmaceutically acceptable residual amounts ofenzyme-friendly organic solvent(s) are within the scope of the presentinvention.

Process step bb) may be performed at a temperature between about 15° C.and about 60° C. Performing process step bb) at ambient temperature(i.e. room temperature, approximately between about 20° C. and about 30°C.), is preferred. Examples of suitable enzyme-friendly organic solventsinclude acetone, 2-butanol, tert.-butanol, chloroform, dichloromethane,ethanol, methanol, 1-propanol, 2-propanol and mixtures of said solvents.Acetone, ethanol and 2-propanol or their mixtures are preferred asenzyme-friendly organic solvents. Acetone is most preferred. Theforegoing list of enzyme-friendly organic solvents in process step bb.)is not meant to be exhaustive but merely illustrative, as a person orordinary skill in the art would understand that many otherenzyme-friendly organic solvents or combination of solvents could alsobe used.

The enzyme-friendly organic solvent is typically used in an amountbetween about 6 and about 10 times, preferably between about 7 and about8 times, the weight of the non-solvent coating constituents used toprepare the pancreatin micropellets. For example, if the non-solventcoating constituents make up to a total weight of about 1.5 g, thenabout 9 g to about 15 g of enzyme-friendly organic solvent may be usedin process step aa).

In process step cc.) the temperature of the pancreatin micropellet core,in one embodiment, is usually maintained between about 30° C. and about60° C. while coating, preferably between about 32° C. and about 55° C.,more preferred between about 35° C. and about 50° C., most preferablybetween about 37° C. and about 49° C. In process step cc.), when cetylalcohol or both cetyl alcohol and triethyl citrate are used thetemperature of the pancreatin micropellet core is maintained betweenabout 40° C. and about 46° C. Maintaining the temperature of thepancreatin micropellet cores within the preferred temperature rangeswhile coating results in improved gastric-acid resistant properties ofthe pancreatin micropellets, in particular when the enteric coatingcomprise cetyl alcohol and triethyl citrate as plasticizers. The coatingin process step cc.) can be accomplished by any process or method knownto a person of ordinary skill in the art. Spray coating is preferred.Usually, process step cc.) is performed in a way that the entericcoating comprises between about 20% and about 30% by weight, preferablybetween about 22% and about 26% by weight and more preferably betweenabout 22.5% and about 25% by weight of the total composition of thepancreatin micropellet. The exact parameters to be applied in processstep cc.) to achieve the desired enteric coating will depend on thecoating technique used. The person skilled in the art understands how toachieve coating films of a desired thickness when using differentcoating techniques.

Drying of the enteric-coated pancreatin micropellet cores in processstep dd) is performed between about 30° C. and about 90° C. preferablybetween about 30° C. and about 55° C., preferably between about 35° C.and about 50° C., and for a period of between about 1 hour and about 60hours, between about 6 hours and about 60 hours, preferably for a periodof between about 6 hours and about 36 hours.

The invention further provides a CRPC which is an enteric coated oraldosage form of an acid-labile drug, in particular of pancreatin, whichis obtainable by the process or its variants described herein. If theCRPC is a pancreatin micropellet or pancreatin microsphere, thepreferred a diameter is about 0.6 to about 2.1 mm and preferrablybetween about 0.7 mm and 1.6 mm.

In one embodiment, oral CRPCs are described wherein pancreatin is theacid-labile drug for delivery to an area of the GI tract having a pHgreater than the pH of the stomach, specifically to the small intestine,usually to the duodenum, of mammals such as humans. The oral CRPCscomprising pancreatin are particularly suited for the prophylaxis and/ortreatment of digestive disorders of different origins like maldigestionand/or for the prophylaxis and/or treatment of pancreatitis, cysticfibrosis, diabetes type I, diabetes type II and/or other conditionsresulting from pancreatine exocrine insufficiency in mammals and humans.

Maldigestion in mammals such as humans is usually based on a deficiencyof digestive enzymes, in particular on a deficiency of endogenouslipase, but also of protease and/or amylase. The cause of such adeficiency of digestive enzymes is frequently a hypofunction of thepancreas (e.g. pancreatic insufficiency, usually known as pancreaticexocrine insufficiency), the organ which produces the largest quantityof, and the most important, endogenous digestive enzymes. If thepancreatic insufficiency is pathological, it may be congenital oracquired. Acquired chronic pancreatic insufficiency may, for example,result from alcoholism. Congenital pancreatic insufficiency may, forexample, result from disease such as cystic fibrosis. The consequencesof the deficiency of digestive enzymes may be severe symptoms ofunder-nutrition and malnutrition, which may be accompanied by increasedsusceptibility to secondary illnesses. In one specific embodiment,pancreatin micropellets according to the invention are thereforeparticularly suited for treating pancreatic exocrine insufficiency ofany origin.

In another embodiment, an enteric coated oral dosage form of pancreatinis provided as previously described, for the manufacture of a medicamentfor the treatment of medical conditions such as digestive disorders,pancreatic exocrine insufficiency, pancreatitis, cystic fibrosis,diabetes type I and/or diabetes type II.

In yet another embodiment, a method is provided for the treatment of amedical condition such as digestive disorders, pancreatic exocrineinsufficiency, pancreatitis, cystic fibrosis, diabetes type I and/ordiabetes type II by administering a therapeutically effective amount ofan enteric coated oral dosage form of pancreatin to a person in need ofsuch treatment.

The CRPCs described herein comprise enteric coated capsules, granules,granulates, micropellets, microspheres, microtablets, pellets, pills,powders and/or tablets. Enteric coated granules, granulates,micropellets, microspheres, pellets, pills or powders, if desired may befilled into capsules or sachets or may be compressed to formmicrotablets or tablets. Equally, uncoated granules, granulates,micropellets, microspheres, pellets, pills or powders may be firstcompressed to form microtablets or tablets which may then be coated withthe enteric coating as provided according to the invention. Microtabletsor tablets may likewise be filled into capsules. Capsules or sachetsmaybe opened to permit mixing of the contents with compatible foods orliquids to facilitate administration of the contents of the capsule orsachet.

Granules are asymmetric agglomerates of powder particles cementedtogether and having no regular geometric form. The surface of thegranule may be spherical, rod-shaped or cylindrical and is usuallyuneven and ridged. Granules are preferably produced by melt or wetgranulation. Granulates are usually defined to be sedimentedagglomerates of granules. Tablets are usually made from the powder orthe granules. Pellets and micropellets can be produced either byexploiting the thermoplastic properties of the excipients in a highshare mixer (melt pelletisation) or by other methods such as extrusion(e.g. melt extrusion or wet extrusion) and spheronisation.Pharmaceutical pellets are usually of a defined geometrical form andhave a generally smooth surface. Specific methods of producingmicropellets or microspheres are described herein. Microspheres andmicropellets are the preferred oral dosage forms described herein.

The enteric coating as disclosed herein will usually be applied to oraldosage forms selected from granules, granulates, micropellets,microspheres, microtablets, pellets, pills, powders and/or tablets andthe coated oral dosage forms may then be incorporated into uncoatedcapsules. However, in an alternative embodiment, the invention alsocomprises enteric coated capsules which contain coated or, morecommonly, uncoated oral dosage forms selected from granules, granulates,micropellets, microspheres, microtablets, pellets, pills, powders and/ortablets. The coated oral dosage forms of the acid-labile drug selectedfrom granules, granulates, micropellets, microspheres, microtablets,pellets, pills, powders and/or tablets or the capsules may further beincorporated into at least one outer package e.g. selected from blistersor bottles. In embodiments of the invention, a pharmaceutical pack orkit is provided comprising one or more containers filled with theingredients of a pharmaceutical composition of the invention. Associatedwith such container(s) can be various written materials such asinstructions for use, or a notice in the form prescribed by agovernmental agency regulating the manufacture, use or sale ofpharmaceuticals products, which notice reflects approval by the agencyof manufacture, use, or sale for human or veterinary administration.

The CRPCs as disclosed herein are substantially free of both monomericphthalic acid ester plasticizers, such as dibutyl phthalate, andsynthetic oils, such as paraffins or mineral oils, while providing thedesired performance in terms of targeted release and storage stability.Further, the CRPCs presently disclosed, in particular in their preferredembodiments, possess superior gastric acid resistance and protectiveproperties, e.g. superior resistance and protective properties in anacidic environment, specifically at pH 1 and/or pH 5. The entericcoating as proposed for the presently disclosed CPRCs have additionaldesirable properties such as dissolution profiles. In preferred CRPCsdisclosed herein, the plasticizer is comprised of cetyl alcohol andtriethyl citrate (CA/TEC-Compositions). CA/TEC-Compositions in generalpreserve a higher lipase content when pancreatin is the acid-labile drugand usually possess a lower water content compared to CRPCs when otherplasticizers are used.

Examples

The following examples are meant to be illustrative and not to limit thepresent disclosure. Other suitable modifications and adaptations are ofthe variety normally encountered by those skilled in the art and arefully within the spirit and scope of the present disclosure.

A. Preparation of an Enteric Coated Oral Dosage Form of an Acid-LabileDrug 1. Preparation of Uncoated Pancreatin Micropellets

15.9 kg of pancreatin was mixed with 3.975 kg of polyethylene glycol4000 in a commercially available high shear mixer and thoroughlymoistened with 3.975 kg of 2-propanol. The resulting mixture wasextruded by means of a commercially available extruding press which wasequipped with a piercing die having 0.8 mm internal diameter bores and acutting device arranged downstream. The temperature was less than 50° C.while pressing. The extruded mass was cut into extrudate fragments ofapproximately 5 mm length by means of the cutting device.

The resulting 14.64 kg of the extrudate fragments were transferred infour portions of roughly equal size to a commercially available roundingapparatus and rounded to give approximately elliptically orapproximately spherically shaped micropellet cores. An additional 135 gof 2-propanol was added while rounding.

After drying in a commercially available continuous vacuum dryer (Vötschtype) at a temperature in a range from between 35° C. and 50° C. for 12hours, the pancreatin micropellets were graded, first with a 3.15 mmsieve (sieving of oversize grain>3.15 mm) and then with a 0.7 mm sieve(sieving of undersize grain<0.7 mm) and afterwards with a 1.25 mm sieve(sieving of oversize grain>1.25 mm) to yield 11.98 kg of pancreatinmicropellet cores having a pancreatin content of 80° A) and a bulkdensity of 0.67 g/ml.

2. Enteric Coating of Pancreatin Micropellet Cores

A coating solution was prepared by adding 1623.2 g of hydroxypropylmethylcellulose phthalate (HP 55), 90.2 g of triethyl citrate, 34.3 g ofcetyl alcohol and 38.9 g of dimethicone 1000 to 14030 g of acetone atroom temperature while stirring.

5025 g of pancreatin micropellet cores (prepared analogously to theprocess as described herein) were fed into a commercially availablefluid bed coater and were spray-coated at a spray rate of 97-101 kg/hand an air pressure of 1.7 bar with the coating solution as preparedabove until the desired film-thickness of the coating had been reached.The product temperature of the pancreatin micropellet cores wasmonitored and maintained in the range between about 37° C. and about 43°C. during coating. The resulting pancreatin micropellets were then driedin a commercially available vacuum dryer (Vötsch type) at a temperaturein a range between 35° C. and 50° C. for 12 hours. The dried pancreatinmicropellets were then graded, first with a 0.7 mm sieve (sieving ofundersize grain<0.7 mm) and then with a 1.6 mm sieve (sieving ofoversize grain>1.6 mm) to yield 6532 g of pancreatin micropellets havinga pancreatin content of about 60% relative to the enteric-coatedpancreatin micropellets. The bulk density of the pancreatin micropelletswas about 0.69 g/ml.

Further pancreatin micropellets were prepared according to the proceduredescribed above and different coatings were applied in a manner similarto the coating process set forth above to yield further CRPCs. Thecompositions of the further CRPCs and other compositions are set forthin Table 1 along with certain process parameters from their respectivecoating processes. Composition G can be produced according to processesas described in U.S. Pat. No. 5,378,462. Comparative composition H wasprepared according to a process which includes dibutylphthalate used asa plasticizer in the coating. All batches have been produced inlaboratory scale unless otherwise noted.

TABLE 1 Pancreatin containing compositions Composition Ingredientsmg/capsule A B C D 1 2 Micropellet Pancreatin 150.00 150.00 150.00150.00 150.00 150.00 Cores PEG 4000 37.50 37.50 37.50 37.50 37.50 37.50Enteric HP 55 48.60 48.60 48.60 48.60 48.60 48.60 Coating Dimethicone1.25 1.25 1.25 1.25 1.25 1.25 (film) TEC 0 0 3.0 4.10 5.00 0 CA 0 0.40 00 0 1.00 Sum 237.40 237.75 240.35 241.45 242.4 238.35 Process Pellettemp. 40° C. 40° C. 40° C. 40° C. 40° C. 40° C. parameters while coatingComposition Ingredients mg/capsule 3 4 5 6* 7 8 Micropellet Pancreatin150.00 150.00 150.00 150.00 150.00 150.00 Cores PEG 4000 37.50 37.5037.50 37.50 37.50 37.50 Enteric HP 55 52.60 48.60 48.60 52.25 52.2552.25 Coating Dimethicone 1.25 1.25 1.25 1.25 1.25 1.25 (film) TEC 03.60 3.00 2.90 2.90 2.90 CA 1.15 0.40 1.00 1.10 1.10 1.10 Sum 242.50241.35 241.35 245.00 245.00 245.00 Process Pellet temp. 40° C. 40° C.40° C. 40° C. 30° C. 35° C. parameters while coating CompositionIngredients mg/capsule 9 10 11 12 13 14 Micropellet Pancreatin 150.00150.00 150.00 150.00 150.00 150.00 PEG 4000 37.50 37.50 37.50 37.5037.50 37.50 Enteric HP 55 56.34 56.34 56.34 52.25 52.25 56.34 CoatingDimethicone 1.35 1.35 1.35 1.25 1.25 1.35 (film) TEC 3.13 3.13 3.13 2.902.90 3.13 CA 1.19 1.19 1.19 1.10 1.10 1.19 Sum 249.51 249.51 249.51245.00 245.00 249.51 Process Pellet temp. 37° C. 40° C. 43° C. 49° C.40° C. 46° C. parameters while coating Composition Ingredientsmg/capsule 15 E F G H Micropellet Pancreatin 128.06 150.00 150.00 150.00150.00 Cores PEG 4000 32.01 37.50 37.50 37.50 37.50 Light mineral oil 00 0 3.75 0 Enteric HP 55 48.10 48.60 48.60 48.60 48.60 CoatingDimethicone 1.15 1.25 1.25 1.25 1.25 (film) TEC 2.67 1.00 2.00 0 0 CA1.01 0 0 0 0 DBP 0 0 0 4.10 4.10 Light mineral oil 0 0 0 3.30 0 Sum213.00 238.35 239.35 248.50 241.50 Process Pellet temp. n.a. 40° C. 40°C. 40° C. 40° C. parameters while coating Table 1 (continued); PEG =polyethylene glycol; TEC = triethyl citrate; CA = cetyl alcohol; HP 55 =hydroxypropyl methylcellulose phthalate; temp. = temperature; DBP =dibutyl phthalate; *= production scale; n.a: data not available.Compositions A, B, C, D, E, F, G and H are comparative compositions.Composition G is a currently available high-quality pharmaceuticalcomposition comprising pancreatin and light mineral oil. CompositionsNo. 6, 10, 13, 14 and 15 are examples of compositions containing CA/TECas the plasticizer. Composition No. 3 is an example of a compositioncomprising cetyl alcohol as the plasticizer.

B. Determination of the Gastric Acid Resistance of Enteric CoatedPancreatin Micropellets at pH 1 and pH 5

The resistance to gastric acid of the pancreatin micropellets of Table1.

Resistance to gastric juice (pH 1) of the different pancreatinmicropellets from Table 1 was determined by immersing the micropelletsfor 2 hours in 0.1 mol/l hydrochloric acid in a disintegration testeraccording to the European Pharmacopoeia (Ph. Eur.). Then theun-dissolved portion of the pellets was separated from the solution andtheir residual lipase activity was determined according to the lipaseassay of Ph. Eur./The International Pharmaceutical Federation” (FIP), POBox 84200; 2508 AE The Hague; The Netherlands. The results of thesetests for gastric resistance of the enteric coating are presented inTable 2 (“stability at pH 1”).

Further, a similar test at pH 5 was performed using the same conditionsas outlined above, with the exception that a phosphate buffer pH 5.0(2.0 g sodium chloride and 9.2 g sodium di-hydrogen phosphatemonohydrate per liter adjusted to pH 5.0) was used as a solvent insteadof 0.1 mol/l hydrochloric acid. The results of these tests for gastricresistance are also presented below in Table 2 (“stability at pH 5”).

The gastric acid resistances of the compositions from Table 1 (seeabove) are each given in Table 2 as percentages of the residuallipolytic activity after the incubation in relation to the actuallipolytic activity of the samples tested prior to the incubation(relative gastric acid resistance). The lipolytic activity is determinedaccording to the lipase assay described in the USP monograph“pancrelipase delayed-release capsules”. In principle, any standardizedand characterized pancreatin sample may be used as the lipase referencestandard. For example, a predetermined lipolytic activity standard maybe obtained from the “International Pharmaceutical Federation” (FIP), POBox 84200; 2508 AE The Hague; The Netherlands. For the purposes of thepresent invention, an internal pancreatin standard was used which isavailable on request from Solvay Pharmaceuticals GmbH,Hans-Boeckler-Allee 20, 30173 Hannover, Germany.

TABLE 2 Relative gastric acid resistances (stabilities) of compositionsin Table 1 at pH 1 and pH 5 Stability at pH 5 Stability at pH 1Composition [%] [%] A 15.3 15.9 B 63.2 53.8 C 71.6 84.2 D 52.0 93.6  187.0 96.0  2 76.4 92.6  3 92.1 94.5  4 85.3 93.7  5 92.0 93.0  6 94.999.4  7 67.4 89.8  8 80.5 95.2  9 83.8 90.8 10 97.9 99.6 11 89.0 93.5 1283.7 94.8 13 100.2 102.7 14 93.6 98.7 E 48.6 65.0 F 36.5 75.0 G 98.6100.6

Preferred CRPCs have a gastric acid resistance (stability) at pH 1 of atleast 75%, in particular of at least 85%, preferably of at least 90%,more preferred of at least 95%, relative to a predetermined pancreatinlipolytic activity standard.

Other preferred CRPCs as disclosed herein have a gastric acid resistanceat pH 5 of at least 75%, in particular of at least 85%, preferably of atleast 90%, more preferred of at least 95%, relative to a predeterminedpancreatin lipolytic activity standard.

CRPCs which are most preferred have a gastric acid resistance at pH 1 ofat least 90% and an additional gastric acid resistance at pH 5 of atleast 90%, relative to a predetermined pancreatin lipolytic activitystandard.

C. Determination of the Dissolution Profile of Enteric Coated PancreatinMicropellets

The dissolution profile of different compositions from Table 1 (seeabove) was determined according to a test procedure as described in theUnited States Pharmacopoeia (USP) monograph “pancrelipasedelayed-release capsules” with increased gastric resistance phase whichis hereby incorporated by reference.

The determination of the resistance to gastric fluid was performed usinggastric juice without enzymes according to USP under standardizedconditions (37° C., 100 rpm) for 2 hours in the dissolution apparatus(basket apparatus USP). Then the un-dissolved portion of the entericcoated pancreatin micropellets was separated from the solution andtransferred into the paddle apparatus according to USP, filled withphosphate buffer solution at pH 6.0 to determine the dissolution ofenzymes. The enteric coated pancreatin micropellets were agitated in adissolution tester under standardized conditions for usually 90 minutes(see exact timepoints in Table 3 below) at 37° C. and 50 rpm.

The lipase activity was determined after selected time points (see Table3) according to the lipase assay described in the USP monograph“pancrelipase delayed-release capsules”.

Further, a test similar to that described above was performed with a“McIlvain buffer” (pH 6.0; for preparation mix solution A: 7.098 gNa₂HPO₄ anhydrous and 4 g of bile salts in 1000 ml water with solutionB: 5.25 g C₆H₈O₇.H₂O and 4 g of bile salts in 100 ml water) instead of aUSP-compliant phosphate buffer. All other conditions remained asdescribed above for the USP-compliant phosphate buffer.

The results of the dissolution profile tests are presented below as “%residual lipase activity of actual lipase activity” for the test seriesperformed with USP-compliant phosphate buffer (see Table 3a) and for thetest series performed with McIlvain buffer (see Table 3b).

TABLE 3a Dissolution profiles of the enteric coated pancreatinmicropellets in phosphate buffer Time % lipase activity of initialpoints actual activity for each composition No. [min.] G 2 3 4 5 13 14 50.0 — 3.0 — 0.0 4.6 NA 10 0.0 — 4.9 — 6.2 4.6 15.37 15 11.9 — 16.4 —37.8 17.6 34.38 20 48.0 — 39.3 — 63.5 40.8 NA 25 62.3 — 59.0 — 72.4 59.8NA 30 73.5 — 67.8 — 80.0 66.2 73.86 45 77.1 — 80.5 — 84.0 76.6 84.45 6079.9 — 77.8 — 84.2 81.9 81.25 75 78.4 — 77.1 — 78.9 79.8 80.40 90 78.2 —72.3 — 77.2 77.4 NA

TABLE 3b Dissolution profiles of the enteric coated pancreatinmicropellet in McIlvain buffer Time % lipase activity of initial pointsactual activity for each composition No. [min.] G 2 3 4 5 13 5 0.0 1.00.5 0.4 0.0 0.7 10 0.5 8.8 1.7 7.7 4.5 1.2 15 6.3 39.6 9.8 39.1 30.2 8.120 23.6 60.5 24.3 62.7 65.6 24.6 25 47.2 68.7 40.6 79.6 79.3 43.1 3066.3 75.2 58.3 84.7 85.2 58.9 45 88.1 76.9 75.4 86.3 87.5 83.7 60 91.074.0 80.9 84.5 85.4 87.1 75 88.4 73.9 81.4 80.2 — 87.1 90 — 71.2 80.6 —— 85.4 105 — — 77.7 — — —

For the dissolution profile test results as provided in Tables 3a and3b, a comparison of the compositions nos. 2, 3, 4, 5 and 13 wasperformed in each case with the reference composition “G”. Thecomparison was based on the “Guidance for Industry”, SUPAC-MR, ModifiedRelease Solid Oral Dosage Forms (September 1997), which is herebyincorporated by reference, by calculating the similarity factor (f2).The two acceptance limits for determining similarity of two comparedcurves were (i) a factor (f2)>50 and (ii) the average deviation at anydissolution sampling point should not be greater than 15%.

In vitro dissolution profile comparisons can be made using a modelindependent approach using similarity factor. Dissolution profiles maybe compared using the following equation that defines a similarityfactor (f₂):

f ₂=50 log{[1+1/nΣ ^(n) _(t=1)(R _(t)-T _(t))²]^(−0.5)*100}

where log=logarithm to base 10, n=number of sampling time points,Σ=summation over all time points, R_(t)=dissolution at time point t ofthe reference (unchanged drug product, i.e. prechange batch),T_(t)=dissolution at time point t of the test (changed drug product,i.e., post-change batch).For comparison of multipoint dissolutionprofiles obtained in multiplemedia, similarity testing should be preformed using pairwise dissolutionprofiles (i.e., for the changed and unchanged product) obtained in eachindividual medium. An f₂ value between 50 and 100 suggests thedissolution profiles are similar.

When applying the above-stated acceptance limits for determiningsimilarity it was found that the dissolution profiles of pancreatinmicropellet CRPCs no. 2, 4 and 5 (see Table 1) could not be consideredto be similar to the dissolution profile of the reference pancreatinmicropellet “G” (see Table 1). However, when applying the above-statedacceptance limits for determining similarity it was found that thedissolution profiles of pancreatin micropellet CRPCs no. 3 and 13 (seeTable 1) could be considered to be similar to the dissolution profile ofthe reference pancreatin micropellet “G” (see Table 1). Thus,pharmaceutical compositions containing pancreatin and their methods ofmanufacturing which are similar to composition G in Table 1 arespecifically described herein.

D. Storage Stability Studies for Enteric Coated Pancreatin MicropelletCPRCs

For determining storage stability of different pancreatin micropelletsfrom Table 1 (see above), hard gelatin capsules of size 0 were filledwith approximately 497 mg of pancreatin micropellets (see Table 1) andpacked into 30 ml HDPE bottles for performing the following tests.

The packed pancreatin micropellets were stored for 5 months under normalor two different aggravated storage conditions (see below for details)and the residual lipase activity was determined in each case analogouslyto the instructions of Ph. Eur. The results of these storage stabilitytests of the CPRCs after 5 months' storage periods are presented belowin Tables 4a and 4b, respectively (“Lipase”).

Resistance to gastric juice (pH 1) of the different pancreatinmicropellets from Table 1 was also determined after a total storageperiod of 5 months by immersing pancrelipase delayed-release pellets for2 hours in 0.1 mol/I hydrochloric acid in a disintegration testeraccording to the Ph. Eur. (Section 2.9.1. “disintegration”). Theun-dissolved portion of the pellets was then separated from the solutionand their residual lipase activity was determined according to thelipase assay of Ph. Eur. (monograph “pancreas powder”). The results ofthese tests for gastric resistance of the enteric coating after 5months' storage periods under normal or two different aggravated storageconditions are presented in Tables 4a and 4b, respectively (“gastricresistance at pH 1”).

Further, a similar test at pH 5 was done using the same conditions asoutlined in the previous paragraph, with the exception that a phosphatebuffer pH 5.0 (2.0 g sodium chloride and 9.2 g sodium di-hydrogenphosphate monohydrate per liter adjusted to pH 5.0) was used as asolvent instead of 0.1 mol/l hydrochloric acid. The results of thesetests for gastric resistance of the enteric coating after 5 months'storage periods are presented below in Tables 4a and 4b, respectively(“gastric resistance at pH 5”).

TABLE 4a Stability results for select compositions from Table 1 at 30°C. and 65% rel. humidity (slightly aggravated storage conditions) %lipase activity of initial activity CPRC Months Conditions No. 0 5Lipase (initial activity) G 100 92  3 100 88 13 100 94 Gastricresistance at pH 1 G 101 91 (actual activity)  3 95 95 13 103 99 Gastricresistance at pH 5 G 99 92 (actual activity)  3 92 86 13 100 95

TABLE 4b Stability results for select compositions from Table 1 at 40°C. and 75% rel. humidity (aggravated storage conditions) % lipaseactivity of initial activity CPRC Months Conditions No. 0 1 2 3 4 5Lipase G 100 90 80 77 69 64 (initial activity)  3 100 87 79 69 64 61 13100 97 87 81 73 67 Gastric resistance at G 101 96 101 94 96 96 pH 1(actual activity)  3 95 94 94 96 87 86 13 103 95 97 97 96 89 Gastricresistance at G 99 92 95 76 87 40 pH 5 (actual activity)  3 92 86 78 6351 22 13 100 90 83 73 43 15

The data presented in Tables 4a and 4b illustrate that the testedcomposition Nos. G, 3 and 13 (see Table 1) are of satisfactory storagestability under normal and slightly aggravated storage conditions over a5 months storage period. The lipase content of composition No. 13,although similar to the two comparative compositions, was best preservedover the observed 5 months' periods under slightly aggravated andaggravated storage conditions.

Under slightly aggravated storage conditions, which are most relevant inpractice, composition No. 13 performed best in terms of gastricresistance at pH 1 and pH 5 over the observed 5 months' periods.

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference to the sameextent as if each reference there individually and specificallyindicated to be incorporated by reference were set forth in its entiretyherein.

In the present disclosure, where numeric values are given as ranges, therespective range limits are generally meant to be included in and beingpart of the given ranges unless expressly stated otherwise.

The use of the terms “a” and “an” and “the” and similar references inthe context of this disclosure (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. All methods described herein can be performed in any suitableorder unless otherwise indicated herein or otherwise clearlycontradicted by context. The use of any and all examples, or exemplarylanguage (e.g., such as, preferred, preferably) provided herein, isintended merely to further illustrate the content of the disclosure anddoes not pose a limitation on the scope of the claims. No language inthe specification should be construed as indicating any non-claimedelement as essential to the practice of the invention.

Alternative embodiments of the claimed invention are described herein,including the best mode known to the inventors for carrying out theclaimed invention. Of these, variations of the disclosed embodimentswill become apparent to those of ordinary skill in the art upon readingthe foregoing disclosure. The inventors expect skilled artisans toemploy such variations as appropriate, and the inventors intend for theinvention to be practiced otherwise than as specifically describedherein.

Accordingly, this invention includes all modifications and equivalentsof the subject matter recited in the claims appended hereto as permittedby applicable law. Moreover, any combination of the above describedelements in all possible variations thereof is encompassed by theinvention unless otherwise indicated herein or otherwise clearlycontradicted by context.

The use of individual numerical values are stated as approximations asthough the values were preceded by the word “about” or “approximately”unless clearly indicated by context otherwise. Similarly, the numericalvalues in the various ranges specified in this application, unlessexpressly indicated otherwise, are stated as approximations as thoughthe minimum and maximum values within the stated ranges were bothpreceded by the word “about” or “approximately.” In this manner,variations above and below the stated ranges can be used to achievesubstantially the same results as values within the ranges. As usedherein, the terms “about” and “approximately” when referring to anumerical value shall have their plain and ordinary meanings to a personof ordinary skill in the art to which the claimed subject matter is mostclosely related or the art relevant to the range or element at issue.The amount of broadening from the strict numerical boundary depends uponmany factors. For example, some of the factors which may be consideredinclude the criticality of the element and/or the effect a given amountof variation will have on the performance of the claimed subject matter,as well as other considerations known to those of skill in the art. Asused herein, the use of differing amounts of significant digits fordifferent numerical values is not meant to limit how the use of thewords “about” or “approximately” will serve to broaden a particularnumerical value. Thus, as a general matter, “about” or “approximately”broaden the numerical value. Also, the disclosure of ranges is intendedas a continuous range including every value between the minimum andmaximum values plus the broadening of the range afforded by the use ofthe term “about” or “approximately”. Thus, recitation of ranges ofvalues herein are merely intended to serve as a shorthand method ofreferring individually to each and every separate value falling withinthe range, unless otherwise indicated herein, and each separate value isincorporated into the specification as if it were individually recitedherein.

1. A process for the manufacture of pancreatin micropellets, comprisingthe steps of: a. providing pancreatin micropellet cores wherein thepancreatin micropellet cores are substantially free of synthetic oils;b. providing an enteric coating solution comprising i. one or more filmforming agents; ii. a plasticizer in an amount greater than about 1.5%by weight relative to the one or more film-forming agents wherein theplasticizer is substantially free of monomeric phthalic acid esters; andiii. optionally, at least one anti-sticking agent, and iv. one or moreenzyme-friendly organic solvent(s); c. coating the pancreatinmicropellet cores with the enteric-coating solution wherein thetemperature of the pancreatin micropellet cores during coating is keptat a temperature suitable to applying the enteric-coating solution; andd. drying the coated pancreatin micropellet cores. 2.-12. (canceled) 13.A method of treating a medical condition in a mammalian subject,comprising the steps of: a. providing pancreatin micropelletsmanufactured according to the process of claim 1 in a dosage formsuitable for oral administration; and b. orally administering the dosageform to the subject to provide pancreatin in an amount sufficient totreat the medical condition; wherein the medical condition is selectedfrom the group consisting of: pancreatic exocrine insufficiency,pancreatitis, cystic fibrosis, diabetes type I and diabetes type II. 14.(canceled)
 15. A pharmaceutical composition, prepared by a processcomprising the steps of: a. preparing an extrudable mixture comprising:i. about 10% to about 95% pancreatin; ii. about 5% to about 90% of atleast one pharmaceutically acceptable binding agent; iii. 0% to about10% of at least one pharmaceutically acceptable excipient; and iv. oneor more enzyme-friendly organic solvents in an amount sufficient to forman extrudable mixture; wherein the percentages of components are weightto weight of the extrudable mixture; b. creating pancreatin micropelletcores from the extrudable mixture; c. forming the pancreatin micropelletcores into approximately spherical or approximately ellipsoidal shape inthe presence of additional enzyme-friendly organic solvent; d. removingthe one or more enzyme-friendly organic solvents from the pancreatinmicropellet cores such that the pancreatin micropellet cores aresubstantially free of the one or more enzyme-friendly organic solvents;wherein the pancreatin micropellet cores are substantially free ofsynthetic oils; e. coating the pancreatin micropellet cores with anenteric-coating solution wherein the temperature of the pancreatinmicropellet cores during coating is kept at a temperature suitable toapply the enteric-coating solution and wherein the enteric-coatingsolution is substantially free of monomeric phthalic acid esters; f.drying the coated pancreatin micropellet cores; and g. placing thecoated pancreatin micropellet cores in a dosage form suitable for oraladministration.
 16. The process of claim 15 wherein the pancreatin ispresent between about 70% and about 90% weight to weight of thepancreatin micropellet cores.
 17. The process of claim 15 wherein thebinding agent is present between about 10% and about 30% weight toweight of the pancreatin micropellet cores.
 18. The process of claim 15wherein the binding agent is selected from the group consisting of:polyethylene glycol 1500, polyethylene glycol 2000, polyethylene glycol3000, polyethylene glycol 4000, polyethylene glycol 6000, polyethyleneglycol 8000, polyethylene glycol 10000, hydroxypropyl methylcellulose,polyoxyethylen, copolymers of polyoxyethylen-polyoxypropylen andmixtures of said organic polymers.
 19. The process of claim 15 whereinthe binding agent is polyethylene glycol
 4000. 20. The process of claim15 wherein the at least one pharmaceutically acceptable excipient isselected from the group consisting of: magnesium stearate, calciumstearate, stearic acid, talcum, starch, calcium phosphate, corn starch,dextrans, dextrin, hydrated silicon dioxide, microcrystalline cellulose,kaolin, lactose, mannitol, polyvinyl pyrrolidone, precipitated calciumcarbonate, sorbitol, silicic acid, alginic acid, amylose, calciumalginate, calcium carbonate, formaldehyde gelatin, pectic carbonate,sago starch, sodium bicarbonate and glycerol.
 21. The process of claim15 wherein the one or more enzyme-friendly organic solvents are presentbetween about 15% and about 35% by weight relative to the amount ofpancreatin.
 22. The process of claim 15 wherein the one or moreenzyme-friendly organic solvents is selected from the group consistingof: acetone, chloroform, dichloro-methane, methanol, ethanol,1-propanol, 2-propanol, 2-butanol, tert-butanol and mixtures of saidsolvents.
 23. The process of claim 15 wherein the one or moreenzyme-friendly organic solvents is 2-propanol.
 24. The process of claim15 wherein removing the one or more enzyme-friendly organic solventsfrom the pancreatin micropellet cores is by drying at a temperaturebetween about 30° C. and about 75° C.
 25. A pharmaceutical composition,prepared by a process comprising the steps of: a. providing pancreatinmicropellet cores wherein the pancreatin micropellet cores aresubstantially free of synthetic oils; b. providing an enteric-coatingsolution comprising i. at least one film-forming agent ii. a plasticizerin an amount of greater than about 1.5% by weight relative to the one ormore film-forming agents film-forming agents wherein the plasticizer issubstantially free of monomeric phthalic acid esters; and iii.optionally at least one anti-sticking agent in one or moreenzyme-friendly organic solvent; c. coating the pancreatin micropelletcores with the enteric-coating solution wherein the temperature of thepancreatin micropellet cores during coating is kept at a temperaturesuitable to apply the enteric-coating solution; and d. drying the coatedpancreatin micropellet cores; and e. placing the coated pancreatinmicropellet cores in a dosage form suitable for oral administration. 26.The composition of claim 25 wherein the enteric coating is between about20% and about 30% by weight of the pancreatin micropellets.
 27. Thecomposition of claim 25 wherein the one or more film-forming agents isselected from the group consisting of: agar, carbomer polymers,carboxymethyl cellulose, carboxymethylethyl cellulose, carrageen,cellulose acetate phthalate, cellu-lose acetate succinate, celluloseacetate trimelliate, chitin, corn protein extract, ethyl cellulose, gumarabic, hydroxypropyl cellulose, hydroxypropylmethyl acetate succinate,hydroxypropyl methylcellulose acetate succinate, hydroxypropylmethyl-cellulose phthalate, methacrylic acid-ethylmethacrylate-copolymer, methyl cellulose, pectin, polyvinyl acetatephthalate, polivinyl alcohol, shellac, sodium alginate, starch acetatephthalate, styrene/maleic acid copolymer and mixtures of saidfilm-forming polymers.
 28. The composition of claim 25 wherein theplasticizer is selected from the group consisting of: saturated linearmonohydric alcohols having 12 to 30 carbon atoms, lauryl alcohol,tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol,heptadecyl alcohol, stearyl alcohol, nonadecyl alcohol, arachic alcohol,behenyl alcohol, carnaubyl alcohol, ceryl alcohol, corianyl alcohol,melissyl alcohol, acetyl tributyl citrate, dibutyl sebacate, fatty acidesters of glycerol, glycerol, polyethylene glycol, propyleneglycol,sorbitan fatty acids, triacetin, triethyl citrate and mixtures of any ofsaid plasticizers.
 29. The composition of claim 25 wherein theplasticizer is cetyl alcohol.
 30. The composition of claim 25 whereinthe plasticizer is triethyl citrate present in an amount of betweenabout 5% and about 20% by weight relative to the film-forming agent. 31.The composition of claim 25 wherein the plasticizer is a mixture ofcetyl alcohol and triethyl citrate which are collectively present in anamount of greater than about 3% by weight relative to the film-formingagent.
 32. The composition of claim 31 wherein the ratio of cetylalcohol to triethyl citrate is between about 0.05:1 and about 1:1 byweight.
 33. The composition of claim 25 wherein the anti-sticking agentis selected from the group consisting of: dimethicone and castor oil.34. The composition of claim 25 wherein the anti-sticking agent ispresent in an amount between about 1.5% and about 3% by weight relativeto the film-forming agent.
 35. The composition of claim 25 wherein theone or more enzyme-friendly organic solvents is selected from the groupconsisting of: acetone, chloroform, dichloro-methane, methanol, ethanol,1-propanol, 2-propanol, 2-butanol, tert-butanol and mixtures of saidsolvents. 36.-43. (canceled)
 44. A pharmaceutical composition, preparedby a process comprising the steps of: a. preparing an extrudable mixturecomprising: i. about 10% to about 95% of an acid labile activepharmaceutical ingredient; ii. about 5% to about 90% of at least onepharmaceutically acceptable binding agent; iii. 0% to about 10% of atleast one pharmaceutically acceptable excipient; and iv. one or moreenzyme-friendly organic solvents in an amount sufficient to form anextrudable mixture; wherein the percentages of components are weight toweight of the extrudable mixture; b. creating micropellet cores from theextrudable mixture; c. forming the micropellet cores into approximatelyspherical or approximately ellipsoidal shape in the presence ofadditional enzyme-friendly organic solvent; d. removing the one or moreenzyme-friendly organic solvents from the micropellet cores such thatthe micropellet cores are substantially free of the one or moreenzyme-friendly organic solvents; wherein the micropellet cores aresubstantially free of synthetic oils; e. coating the micropellet coreswith an enteric-coating solution wherein the temperature of themicropellet cores during coating is kept at a temperature suitable toapply the enteric-coating solution and wherein the enteric-coatingsolution is substantially free of monomeric phthalic acid esters; f.drying the coated micropellet cores; and g. placing the coatedmicropellet cores in a dosage form suitable for oral administration.45.-46. (canceled)